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PubMed2004

Alpha-melanocyte-stimulating hormone through melanocortin-4 receptor inhibits nitric oxide synthase and cyclooxygenase expression in the hypothalamus of male rats.

There is evidence that alpha-melanocyte-stimulating hormone (alpha-MSH) has immunomodulatory and anti-inflammatory actions within the brain. In this study, we tested whether these actions are due to inhibition of the synthesis of nitric oxide (NO) and prostaglandins induced by lipopolysaccharide (LPS). Since melanocortin subtype MC4 receptor has been detected in the hypothalamus, we investigated the effect of central administration of alpha-MSH and HS024 (a selective MC4 receptor antagonist) on the gene expression of inducible, neuronal and endothelial NO synthase (iNOS, nNOS and eNOS) and on cyclooxygenase (COX-1 and COX-2) expression in the mediobasal hypothalamus (MBH) of LPS-treated male Wistar rats. Peripheral administration of LPS (250 microg/rat, 3 h) induced iNOS and COX-2 gene expression in the MBH. This stimulatory effect was reduced by alpha-MSH (3 nmol/rat) injected 30 min before LPS. alpha-MSH and HS024 (1 nmol/rat) alone had no effect on iNOS and COX-2 expression. The action of alpha-MSH on LPS-induced iNOS and COX-2 mRNA levels was not observed in the presence of HS024, suggesting that MC4-R may be involved in the modulatory effect of alpha-MSH. None of these treatments produced any modifications in nNOS, eNOS and COX-1 expression in MBH. The increase in serum corticosterone levels induced by LPS was attenuated by alpha-MSH. Both LPS and alpha-MSH decreased serum LH and prolactin levels. HS024 failed to modify the inhibitory effects of LPS and alpha-MSH on prolactin release but reverted the effect of LPS on LH secretion, indicating that MC4-R activation may be involved in the effects of alpha-MSH on LH secretion in male rats. When we examined the in vitro effect of LPS (10 microg/ml) and LPS plus interferon-gamma (IFN-gamma, 100 ng/ml) on iNOS expression in MBH, an increase in iNOS mRNA levels was observed only in the presence of LPS + IFN-gamma. This stimulatory effect was attenuated in the presence of alpha-MSH (5 microM), which by itself had no effect. No changes were found in nNOS, eNOS, COX-1 or COX-2 expression. These results indicate that alpha-MSH reduces the induction of iNOS and COX-2 gene expression at the hypothalamic level during endotoxemia and suggest that endogenous alpha-MSH may exert an inhibitory tone on iNOS and COX-2 transcription via MC4 receptors acting as a local anti-inflammatory agent within the hypothalamus.

Animals↗
PubMed2004

Estrogen reduces serotonin-1A receptor-mediated oxytocin release and Galpha(i/o/z) proteins in the hypothalamus of ovariectomized rats.

The present study examined the effect of estradiol on hypothalamic serotonin-1A (5-HT(1A)) receptor signaling in female rats. We first examined the time-course effects of a single injection of the 5-HT(1A) receptor agonist (+/-)8-OH-DPAT (5, 15 or 30 min prior to decapitation), and dose response of (+)8-OH-DPAT (50, 100, 200 or 500 microg/kg, s.c.) on plasma hormones in ovariectomized rats that received a daily injection of beta-estradiol 3-benzoate (10 microg/day, s.c.) or vehicle (sesame oil) for 2 days. In vehicle- and estrogen-treated rats, the peak response of hormones occurred at 15 min after injection and the time-course of oxytocin and adrenocorticotropic hormone (ACTH) responses to an injection of 8-OH-DPAT were comparable. However, only the oxytocin response was reduced by estrogen treatment. A second experiment compared the ACTH and oxytocin responses with doses of 50 or 200 microg/kg, s.c. of (+)8-OH-DPAT vs. (+/-)8-OH-DPAT in ovariectomized rats that were treated with oil or beta-estradiol 3-benzoate (10 microg/day, s.c.) for 2 days. (+)8-OH-DPAT and (+/-)8-OH-DPAT produced a similar magnitude of increase in plasma levels of ACTH and oxytocin. Treatment with beta-estradiol 3-benzoate produced a significant and comparable reduction in the oxytocin response to the highest dose (200 microg/kg, s.c.) of both (+)8-OH-DPAT and (+/-)8-OH-DPAT but did not alter the ACTH response to either (+)8-OH-DPAT or (+/-)8-OH-DPAT. In the dose-response experiment, a dose of 50 microg/kg of (+)8-OH-DPAT produced a maximal increase in plasma levels of ACTH, while the maximal oxytocin response was achieved with a dose of 200 microg/kg, s.c. Treatment with beta-estradiol 3-benzoate reduced the maximal oxytocin response to (+)8-OH-DPAT (by 29%) but did not alter the ACTH response to any doses of (+)8-OH-DPAT. To examine potential mechanisms mediating the effects of estrogen on 5-HT(1A) receptor signaling, we measured the levels of Galpha(i), Galpha(o) and Galpha(z) proteins, which couple 5-HT(1A) receptors to their effector enzymes, in two subregions of the hypothalamus. The levels of Galpha(z) protein were reduced in the mediobasal hypothalamus (containing the ventromedial and arcuate nuclei), which mainly expresses estrogen receptor-alpha, but not in the paraventricular hypothalamus, which mainly expresses estrogen receptor-beta. Estradiol reduced the levels of Galpha(i2) and Galpha(i3 )proteins in both hypothalamic regions but did not affect Galpha(i1) levels in either area. Combined, the data suggest that racemic and stereoselective 8-OH-DPAT have similar neuroendocrine effects and that both estrogen receptor-alpha and estrogen receptor-beta mediate the reduction in levels of Galpha(i2,3) proteins.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed2005

The baromodulatory effect of gamma knife irradiation of the hypothalamus in the obese Zucker rat.

OBJECTIVE: The aim of this study was to evaluate the effect on body weight set point over time of focused, subnecrotic doses of radiation via gamma knife (GK) to the hypothalamus of the genetically obese Zucker rat. METHODS: A total of 36 adolescent animals were used in this experiment and placed in 6 groups of 6. The genetically obese homozygous Zucker rat was used in 4 groups (n = 24) and received GK, subcutaneous cobalt protoporphyrin (CoPP), both treatments combined or sham treatment. The heterozygous lean Zucker rat was used in 2 control groups (n = 12) and received either GK or sham treatment. All animals were weighed at the beginning of the experiment and at weekly intervals for 34 weeks. GK irradiation was accomplished using a specially designed stereotactic frame and a total dose of 40 Gy was given to 2 nearby targets in the medial hypothalamus. The drug subgroups received weekly subcutaneous injections. All animals were housed in the same environment with unlimited access to food. RESULTS: There were no significant differences in weight between the lean GK and sham groups. For the obese cohort, beginning at week 7 and throughout the remainder of the experiment, there were significant and sustained reductions in weight set point for animals that received GK (p < 0.05) and CoPP (p < 0.05) compared to sham-treated animals. Curiously, there was no statistical difference between the combined treatment and sham subgroups, though there was a trend toward weight reduction (p < 0.10). With the exception of one animal in the obese GK cohort in which there was a small area of necrosis lateral to the target area, histopathological analysis failed to reveal any abnormalities. There were no gross behavioral abnormalities noted. CONCLUSION: Our experimental results suggest that a single dose of GK irradiation to the hypothalamus can produce sustained reduction in the weight set point without emaciation in adolescent animals. The effect of this treatment is comparable to a well-studied drug therapy with a metalloporphyrin. We hypothesize that this involves a resetting of the hypothalamic set point for body weight through an as yet uncharacterized neuromodulatory effect.

Animals↗
PubMed2005

Stimulation of the posterior hypothalamus for medically intractable impulsive and violent behavior.

OBJECTIVE: To describe the therapeutic effect of deep brain stimulation for the treatment of patients with below-average IQs who are affected by aggressive and disruptive behavior and who are resistant to any drug and/or conservative treatment (including occupational therapy). PATIENTS AND METHODS: Two consecutive patients suffering from mental retardation with aggressive and disruptive behavior and resistant to any pharmacological treatment underwent deep brain stimulation electrode placement in the posteromedial hypothalamus for continuous chronic high-frequency stimulation (HFS). The stereotactic coordinates of the target were chosen according to the study by Sano et al., which involved hypothalamic stereotactic lesions. RESULTS: HFS of the posteromedial hypothalamus demonstrated consistent improvement of disruptive behavior in both patients at the follow-up evaluation 1 year later. CONCLUSIONS: HFS of the posteromedial hypothalamus showed similar results to those obtained by Sano et al. in the 1960s with radiofrequency lesions of the same target volume. The reversibility of neurostimulation allows HFS to control disruptive behavior when conservative treatments are ineffective, and drug therapy is uneventful or causes severe side effects. In conclusion, this neuromodulation procedure improved the quality of life and the range of social relationships for both of the treated patients.

Adult↗
PubMed2005

Identification of sex hormone-binding globulin in the human hypothalamus.

Gonadal steroids are known to influence hypothalamic functions through both genomic and non-genomic pathways. Sex hormone-binding globulin (SHBG) may act by a non-genomic mechanism independent of classical steroid receptors. Here we describe the immunocytochemical mapping of SHBG-containing neurons and nerve fibers in the human hypothalamus and infundibulum. Mass spectrometry and Western blot analysis were also used to characterize the biochemical characteristics of SHBG in the hypothalamus and cerebrospinal fluid (CSF) of humans. SHBG-immunoreactive neurons were observed in the supraoptic nucleus, the suprachiasmatic nucleus, the bed nucleus of the stria terminalis, paraventricular nucleus, arcuate nucleus, the perifornical region and the medial preoptic area in human brains. There were SHBG-immunoreactive axons in the median eminence and the infundibulum. A partial colocalization with oxytocin could be observed in the posterior pituitary lobe in consecutive semithin sections. We also found strong immunoreactivity for SHBG in epithelial cells of the choroid plexus and in a portion of the ependymal cells lining the third ventricle. Mass spectrometry showed that affinity-purified SHBG from the hypothalamus and choroid plexus is structurally similar to the SHBG identified in the CSF. The multiple localizations of SHBG suggest neurohypophyseal and neuroendocrine functions. The biochemical data suggest that CSF SHBG is of brain rather than blood origin.

Aged↗
PubMed1990

Phylogeny of putative cholinergic visual pathways through the pretectum to the hypothalamus in teleost fish.

Three patterns of pretectal organization can be discerned morphologically in teleosts. The taxonomic distribution of these pretectal patterns suggests that the intermediately complex pattern (seen in most teleost groups) has given rise to both the elaborate pattern (seen in percomorphs) and the simple pattern (seen in cyprinids). Two pretectal patterns (intermediately complex and elaborate) form part of similar, homologous visual pathways to the hypothalamus; the third pattern is involved in a nonhomologous pathway to the hypothalamus. Acetylcholinesterase (AChE) histochemistry was used in the present study in order to characterize these pretectal patterns further. It is demonstrated that AChE is a highly selective and reliable interspecific marker for all divisions of the superficial pretectum, the nucleus corticalis, the posterior pretectal nucleus (or nucleus glomerulosus) and portions of the inferior lobe. Therefore, the histochemical data support the hypothesis of a homology between the three patterns of pretectal organization in teleosts. Furthermore, the present data provide a basis for more specific investigations regarding the involvement of acetylcholine as a neurotransmitter within the visual pathways to the hypothalamus in teleosts.

Acetylcholinesterase↗
PubMed1975

Effects of hydrocortisone on biogenic amine levels in the hypothalamus.

Implants of hydrocortisone acetate (HCA), cholesterol or empty tubing were placed in the hypothalamus of rats. Corticoid implants elevated serotonin levels in the basomedial hypothalamus compared to the other two groups, but norepinephrine levels were unchanged. Adrenal and serum cortcosterone, as well as adrenal weight, were lower in animals with hydrocortisone implants. These data support the hypothesis that hypothalamic serotonin is involved in negative feedback control of adrenal steroid secretion. Biogenic amines in the medial hypothalamus were determined at 30 days in rats neonatally treated with HCA. Both norepinephrine and serotonin levels were elevated significantly in the treated group in comparison to controls, but dopamine levels failed to change.

Adrenal Glands↗
PubMed1977

Evidence for the dependence of serum luteinizing hormone surge on a transient, enhanced secretion of gonadotropin-releasing hormone from the hypothalamus.

Data that a substantial, transient release of gonadotropin-releasing hormone (GnRH) from the hypothalamus is a prerequisite for the serum luteinizing hormone (LH) surge are presented. Ovariectomized rats, in which daily afternoon LH peaks can be induced by estradiol benzoate (EB), were used as the experimental model. These rats present a homogenous, synchronized population having low hypothalamic stores of GnRH, thus facilitating detection of small physiological fluctuations in the levels of hypothalamic GnRH. Blockade, by Nembutal administration, of the serum LH surge on 2 consecutive afternoons results in elevated GnRH levels in the hypothalamus (1.79 ng in blocked rats vs 0.94 ng in controls). Abolition of LH secretion by administration of antiserum to GnRH, unlike the Nembutal blockade, does not affect GnRH levels. These results indicate that the afternoon LH surge is dependent on a transitory, enhanced release of GnRH from the hypothalamus, reflected by a depletion of GnRH stores.

Animals↗
PubMed1979

Effect of hypophysectomy and growth hormone administration on somatostatin content in the rat hypothalamus.

The effect of hypophysectomy and bovine GH administration on somatostatin (SRIF) content in the rat hypothalamus was investigated. SRIF content was determined by a specific radioimmunoassay method described elsewhere. The total SRIF content of the rat hypothalamus as well as its content per milligram wet weight had decreased 4 weeks after hypophysectomy but was restored significantly in those rats which were subjected to bovine GH administration for 7 days 3 weeks after hypophysectomy. Furthermore, in nonoperated rats, increase of hypothalamic SRIF content was observed after 7 days GH administration. These results indicate that growth hormone may influence the SRIF content of hypothalamus and it seems likely that a feedback mechanism between pituitary GH and hypothalamic SRIF exists.

Animals↗
PubMed1981

Studies on muscarinic receptors in mouse and rat hypothalamus: a comparison of sex and cyclical differences.

The ligand binding properties of muscarinic receptors present in whole hypothalamus as well as in its three regions (preoptic area, median and posterior regions) were studied in male rats and mice, as well as in female rats during various stages of the estrous cycle, using the tritiated antagonist N-methyl-4-piperidyl benzilate. Kinetic and equilibrium analysis of antagonist binding as well as competition experiments with agonists, were used to probe the nature of the binding sites and possible differences between specific muscarinic sites in the various preparations. We could detect differences in agonist binding parameters between male and female rats in the preoptic area. In female rats binding of agonist to high affinity state is characterized by a lower affinity (27 nM) than in males (3.7 nM). Secondly, the population of agonist high affinity sites at the proestrous stage is much higher than that at other stages of cycle (66 vs. 38%). In addition, the binding properties of muscarinic receptors following intracisternal 6-hydroxydopamine lesion were investigated. This treatment resulted in a decrease of about one sixth of the total muscarinic receptors in the hypothalamus. The data are best interpreted as a degeneration of existing presynaptic muscarinic receptors located on catecholamine terminals in the hypothalamus. The pre- and postsynaptic nature of the muscarinic receptors, their localization in view of their binding properties, and their possible physiological role are discussed.

Animals↗
PubMed1982

GABA neuron systems in hypothalamus and the pituitary gland. Immunohistochemical demonstration using antibodies against glutamate decarboxylase.

The distribution of gamma-aminobutyric acid (GABA) nerve fibers and cell bodies in the rat hypothalamus and pituitary gland was immunohistochemically examined using antibodies against the GABA-synthesizing enzyme glutamate decarboxylase (GAD). The dense network of GAD-positive nerve fibers was observed to be essentially evenly distributed throughout the hypothalamus. A plexus of GABA terminals was also demonstrated both in the median eminence and with in the posterior and intermediate lobes of the pituitary. Three distinct clusters of magnocellular GABA neurons were discovered in the posterior hypothalamus. In the addition, GAD immunoreactive cell bodies were observed in many other hypothalamic nuclei, such as the arcuate nucleus and in the perifornical region. The results provide a morphological basis by which GABA of hypothalamic origin may regulate the neuroendocrine system.

Animals↗
PubMed1984

Corticotropin releasing factor (CRF): origin and course of afferent pathways to the median eminence (ME) of the rat hypothalamus.

8-10 days after making various lesions in the rat hypothalamus, the presence of corticotropin releasing factor (CRF) immunoreactive neural structures was studied in paraffin and vibratome sections with CRF immunocytochemistry. Bilateral anterolateral deafferentation of the medial basal hypothalamus (MBH) caused complete disappearance of CRF immunoreactivity from the median eminence (ME) in brains where the posterior edge of the cut reached the level of the pituitary stalk. A shorter cut resulted in positive immunostaining caudal to the caudal edge of the cut. Unilateral deafferentation of the MBH caused significant decrease in CRF immunostaining in the ipsilateral ME. Unilateral posterolateral deafferentation of the MBH caused no changes in CRF immunostaining in the rostral ME, while fewer CRF-containing processes were observed in the more caudal regions. A horizontal cut ventral to the paraventricular nuclei (PVN) caused a slight decrease in the number of CRF-immunoreactive profiles in the ME. A wider and complete unilateral horizontal cut resulted in a significant decrease in CRF immunoreactivity on the operated side. Following various surgical interventions, hormone accumulation in cell bodies was detected in the paraventricular, periventricular preoptic, dorsomedial, periventricular, lateral and posterior hypothalamic, and premammillary nuclei. Fibers arising from most of these nuclei formed a fan-like projection to the ME. The majority of the CRF-fibers ran through the lateral tract of the fan, and reached the ME by the lateral-basal retrochiasmatic area (LBRCA). Scattered fibers were detected in the lateral-basal hypothalamus as far caudally as the level of the pituitary stalk. Unilateral anterolateral and horizontal cuts did not result in complete disappearance of CRF immunoreactivity from the ipsilateral ME, indicating the existence of CRF-fibers of contralateral origin in the ME.

Animals↗
PubMed1985

Nuclear uptake of estrogens in the male dove hypothalamus: relationship to aromatase activity and behavioral effects.

The natural estrogen, estradiol-17 beta, and a synthetic agonist, diethyl stilbestrol (DES), accumulated selectively in cell nuclei of the male dove preoptic area and posterior hypothalamus following intramuscular injection of the corresponding 3H-labelled tracers. Nuclear incorporation of radioactivity was saturable and specific, as shown by the effect of competition doses of unlabelled estrogens. The non-aromatizable androgen, 5 alpha-dihydrotestosterone (DHT), did not compete with estrogens for nuclear binding sites, indicating that cross-reaction with androgen receptors is unlikely. Estradiol uptake was higher in the preoptic area than in the posterior hypothalamus, whereas DES uptake did not differ significantly between these areas. Although both brain areas are likely to contain specific estrogen receptors, only the preoptic area is known to be directly involved in the control of male precopulatory courtship behavior in the dove. Aromatase activity responsible for the local conversion of testosterone to biologically active estradiol-17 beta, measured in vitro, was also much higher in the preoptic and posterior hypothalamic areas than in adjacent areas of the basal forebrain and hypothalamus. The similarity in localization of aromatase activity and intranuclear uptake of estradiol indicates that the formation of estrogen may occur only within discrete brain areas containing specific estrogen receptors. Intranuclear uptake of DES in the preoptic area, which is half that of estradiol, is correlated with lower effectiveness both in inducing aromatase activity in the preoptic area and in eliciting an estrogen-dependent behavior in castrated males. The effectiveness of estrogens on behavior in the male dove is likely to depend upon characteristics of estrogen receptors in the preoptic area.

Animals↗
PubMed1985

Serotonergic stimulation of prolactin and corticosterone secretion is mediated by different pathways from the mediobasal hypothalamus.

In previous studies we obtained evidence that serotonin release by p-chloroamphetamine (PCA) causes an increase in corticosterone secretion but that this effect is not mediated via the raphe nuclei in the midbrain. In contrast, PCA-induced prolactin secretion was abolished by dorsal raphe lesions. In the present study, posterolateral cuts which interrupted caudal inputs to the hypothalamus attenuated the effect of PCA on plasma prolactin but did not block the PCA-induced increase in plasma corticosterone levels. Large lesions of the mediobasal hypothalamus produced a significant reduction of plasma corticosterone concentration but did not completely prevent the effect of PCA on corticosterone secretion. Hypophysectomy performed 24 h before sacrifice caused a marked decrease in plasma corticosterone levels but did not completely abolish the effect of PCA. These results suggest that PCA also stimulates corticosterone secretion via a direct action on the adrenal gland. The lesions in the mediobasal hypothalamus caused an increase in plasma prolactin concentration, and in these rats, PCA suppressed rather than stimulated prolactin secretion. This suggests that the known weak dopamine agonist activity of PCA is exposed when the effects of serotonin release in the brain are eliminated.

Amphetamines↗
PubMed1988

Activation of 5-HT 1 serotonin receptors in the medial basal hypothalamus stimulates prolactin secretion in the unanaesthetized rat.

Prolactin concentrations were measured in plasma in unanaesthetized male rats chronically prepared with venous and intracerebral cannulae, before and after treatment with bilateral intracerebral injections of serotonin and fenfluramine. Serotonin 1, 5, and 10 nmol injected in the medial basal hypothalamus caused dose-related rises in prolactin concentrations. The secretion of prolactin was blocked by metergoline (2.5 mg/kg i.p.) and only partially by ketanserin (2.0 mg/kg i.v.). The 5-HT 1A agonist 8-OH-DPAT potently stimulated prolactin at doses of 1 and 5 nmol. Fenfluramine 10 and 100 nmol also caused increases in plasma prolactin when injected in the basal hypothalamus. Prolactin secretion was also evoked by serotonin injections in the preoptic/anterior hypothalamic area, but the response was not blocked by serotonin receptor antagonists. It is concluded that activation of 5-HT 1A receptors on or near prolactin-regulating neurons in the arcuate nucleus causes secretion of prolactin. The effectiveness of fenfluramine in increasing plasma prolactin suggests that endogenous serotonin released from terminals in the basal hypothalamus may mediate prolactin secretion physiologically.

Animals↗
PubMed1988

Growth hormone synthesis decreased after anterolateral deafferentation of the medial basal hypothalamus in the rat.

To study the role of the hypothalamus in the regulation of growth hormone (GH) synthesis, the rate of amino acid incorporation into GH in vitro was examined in rats with anterolateral deafferentation of the medial basal hypothalamus. Amino acid incorporation into GH (GH synthesis) decreased significantly 7 days after the deafferentation, although prolactin synthesis did not show any significant fluctuations. The serum GH was increased, while the pituitary GH content was decreased. Somatostatin in the stalk median eminence of such deafferentated animals decreased markedly, while GH-releasing hormone was decreased slightly but not significantly. Immunohistochemical examinations revealed that the number of somatostatin nerve terminals in the median eminence decreased markedly, while GH-releasing hormone nerve terminals in the same area remained intact. These findings suggest that neural factor(s) outside the medial basal hypothalamus plays an important role in the regulation of GH synthesis.

Animals↗
PubMed1988

The anterior hypothalamus provides stimulatory input to tuberoinfundibular dopamine neurons which is not mediated by prolactin.

Complete or retrochiasmatic deafferentations of the mediobasal hypothalamus were made in female rats 7 days prior to experimentation in order to determine the role played by putative afferent neuronal connections (1) in maintaining the basal neuronal activity of tuberoinfundibular dopaminergic (TIDA) neurons, and (2) in the stimulatory actions of prolactin on these neurons. The neuronal activity of TIDA neurons was estimated by measuring the rates of synthesis, turnover or metabolism of dopamine (DA) in the terminals of these neurons in the median eminence. Complete deafferentation of the mediobasal hypothalamus reduced the basal rate of DA synthesis, and retrochiasmatic deafferentation decreased the rates of synthesis, turnover and metabolism of DA in the median eminence. A knife cut 1 mm rostral to the retrochiasmatic cut failed to alter basal TIDA neuronal activity. These results suggest that afferent neuronal inputs originating in or coursing through the caudal portion of the anterior hypothalamus mediate a tonic stimulatory influence on TIDA neurons in the female rat. Intracerebroventricular administration of rat prolactin or systemic administration of haloperidol (which increases circulating levels of prolactin) increased DA synthesis in the median eminence of both sham-operated rats and retrochiasmatic-deafferentated rats. Thus, the stimulatory action of prolactin was not blocked by retrochiasmatic deafferentation. In addition, elimination of the basal stimulatory action of endogenous prolactin by pretreating animals with bromocriptine reduced the rate of DA synthesis in the median eminence of both sham- and retrochiasmatic-deafferentated rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Molecular forms of gonadotropin-releasing hormone associated peptide (GAP): changes within the rat hypothalamus and release from hypothalamic cells in vitro.

We have developed RIAs using antisera directed against the cryptic peptide of the GnRH precursor (termed GnRH-associated peptide, GAP) and have used these together with a GnRH assay to characterize proGnRH-derived peptides in rat hypothalamic extracts. On Sephadex chromatography we have identified three molecular forms of GAP-like immunoreactivity (GAP-LI), in addition to the GnRH decapeptide. The largest of these forms is an 8.0-kilodalton (kD) GAP-LI which appears to be the complete proGnRH peptide. The second is a 6.5-kD GAP-LI, and is similar to the complete cryptic peptide (i.e. proGnRH14-69 or GAP1.56). The third peptide is a 2.5 kD C-terminal fragment of the cryptic peptide, representing a processed form of GAP. In whole hypothalamic extracts from normal rats the 8.0-kD form was the major form, comprising 60-70% of the total GAP-LI. All three forms were present in three distinct areas of the rat hypothalamus, namely median eminence (ME), anterior and mid-hypothalamus. However in the ME the proportion of 8.0-kD GAP-LI was significantly reduced and the proportion of 6.5-kD GAP-LI significantly increased compared to anterior and mid-hypothalamic samples (p less than 0.05). In whole hypothalamic extracts from pregnant and lactating rats the total content of proGnRH-derived peptides was reduced but the relative proportions of these peptides were not significantly changed from normal female rats. However, in postlactating rats, 2 weeks after removal of pups, the total levels of GAP-LI were unchanged compared to normals, but the percentage of 8.0-kD GAP-LI was significantly decreased and the percentage of 2.5-kD GAP-LI significantly increased compared to normals (p less than 0.05), suggesting that proGnRH may undergo additional processing dependent on physiological condition. In fetal and neonatal rats the proportion of the 6.5-kD peptide was increased and that of the 8.0-kD peptide decreased compared to adults, and this change became less significant with increasing age. In ovariectomized rats the proportion of 6.5-kD GAP-LI was increased and that of 8.0-kD GAP-LI decreased; this change was partially reversed with steroid treatment. Both the 6.5 and 2.5-kD forms were released by high K+ stimulation of neonatal hypothalamic cells in culture. These results indicate that there is differential processing of the proGnRH precursor within the hypothalamus and in altered physiological states.

Aging↗